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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Assess the Efficacy and Safety of GS-6624 in Subjects with Idiopathic Pulmonary Fibrosis (RAINIER)

    Summary
    EudraCT number
    		 2012-001571-36
    Trial protocol
    		 IT   BE   GB   DE   CZ   ES   PL  
    Global end of trial date
    23 Feb 2016

    Results information
    Results version number
    		 v1
    This version publication date
    11 Mar 2017
    First version publication date
    11 Mar 2017
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-322-0207
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01769196
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Clinical Trials Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trials Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study are to determine the effect of simtuzumab (GS-6624) on progression-free survival (PFS) as determined by either a categorical decline in forced vital capacity (FVC) or all-cause mortality, in all participants enrolled or in a subset of participants who are classified as lysyl oxidase-like-2 (LOXL2) high based on a prespecified level in serum at baseline.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jan 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 28
    Country: Number of subjects enrolled
    Spain: 24
    Country: Number of subjects enrolled
    United Kingdom: 33
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    Czech Republic: 12
    Country: Number of subjects enrolled
    France: 36
    Country: Number of subjects enrolled
    Germany: 40
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Canada: 24
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Australia: 29
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    United States: 208
    Country: Number of subjects enrolled
    Korea, Republic of: 69
    Worldwide total number of subjects
    544
    EEA total number of subjects
    201
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    189
    From 65 to 84 years
    352
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in North America, Europe, and Asia Pacific. The first participant was screened on 31 January 2013. The last study visit occurred on 23 February 2016.

    Pre-assignment
    Screening details
    		 1250 participants were screened.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Simtuzumab
    Arm description
    		 Simtuzumab 125 mg/mL administered subcutaneously once a week
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simtuzumab
    Investigational medicinal product code
    Other name
    GS-6624
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    125 mg/mL administered once a week

    Arm title
    		 Simtuzumab Placebo
    Arm description
    		 Simtuzumab placebo administered subcutaneously once a week
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simtuzumab Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Simtuzumab placebo administered subcutaneously once a week

    Number of subjects in period 1
    		Simtuzumab Simtuzumab Placebo
    Started
    272
    272
    Completed
    0
    0
    Not completed
    272
    272
         Adverse event, non-fatal
    24
    20
         Death
    21
    26
         Protocol specified criteria for withdrawal
    9
    11
         Study terminated by sponsor
    160
    161
         Protocol Violation
    -
    3
         Investigator's discretion
    7
    3
         Progressive disease
    11
    6
         Withdrew consent
    36
    40
         Lack of efficacy
    3
    2
         Participant never dosed with study drug
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Simtuzumab
    Reporting group description
    		 Simtuzumab 125 mg/mL administered subcutaneously once a week

    Reporting group title
    Simtuzumab Placebo
    Reporting group description
    		 Simtuzumab placebo administered subcutaneously once a week

    Reporting group values
    		 Simtuzumab Simtuzumab Placebo Total
    Number of subjects
    		 272 272 544
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67.7 ( 7.6 ) 68.5 ( 7.07 ) -
    Gender categorical
    Units: Subjects
        Female
    		 45 47 92
        Male
    		 227 225 452
    Race
    Units: Subjects
        Asian
    		 35 36 71
        Black
    		 3 3 6
        White
    		 231 229 460
        Other
    		 3 4 7
    Ethinicity
    Units: Subjects
        Hispanic or Latino
    		 5 7 12
        Not Hispanic or Latino
    		 267 264 531
        Not Permitted
    		 0 1 1
    FVC % Predicted Category
    Units: Subjects
        Mild
    		 37 46 83
        Moderate
    		 152 150 302
        Severe
    		 83 76 159
    Forced vital capacity (FVC) Percent Predicted
    Units: FVC % predicted
        arithmetic mean (standard deviation)
    		 61.4 ( 12.7 ) 62.3 ( 12.22 ) -
    Baseline Serum LOXL2
    Units: pg/mL
        arithmetic mean (standard deviation)
    		 89.8 ( 70.06 ) 86.7 ( 51.99 ) -

    End points

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    End points reporting groups
    Reporting group title
    Simtuzumab
    Reporting group description
    		 Simtuzumab 125 mg/mL administered subcutaneously once a week

    Reporting group title
    Simtuzumab Placebo
    Reporting group description
    		 Simtuzumab placebo administered subcutaneously once a week

    Primary: Progression Free Survival

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    End point title
    		 Progression Free Survival
    End point description
    Progression free survival (PFS) was defined as the categorical decrease in forced vital capacity (FVC) % predicted (≥ 10% relative decrease in FVC and ≥ 5% absolute decrease in FVC from baseline) with confirmation at a consecutive visit at least 2 weeks later using the same criteria. Intent-to-Treat (ITT) Analysis Set
    End point type
    Primary
    End point timeframe
    Up to 148 weeks
    End point values
    		 Simtuzumab Simtuzumab Placebo
    Number of subjects analysed
    272
    272
    Units: Months
        median (confidence interval 95%)
    12.6 (11.3 to 14.4)
    15.4 (12.6 to 19.1)
    Statistical analysis title
    		 Statistical analysis - Simtuzumab vs Placebo
    Statistical analysis description
    The null hypothesis was that there is no difference in PFS between Simtuzumab and Simtuzumab placebo. The alternative hypothesis was that there is a difference. These hypotheses were evaluated using stratified log-rank test, adjusted for screening post-bronchodilator FVC % predicted, sLOXL2 level categories, and concomitant use of pirfenidone or nintedanib (P/N) at time of screening.
    Comparison groups
    Simtuzumab Placebo v Simtuzumab
    Number of subjects included in analysis
    544
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.329
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.45

    Primary: PFS Among the Participants With sLOXL2 ≥ 50th Percentile

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    End point title
    		 PFS Among the Participants With sLOXL2 ≥ 50th Percentile
    End point description
    Participants in the ITT Analysis Set with serum LOXL2 (sLOXL2) ≥ 50th percentile in peripheral blood were analyzed.
    End point type
    Primary
    End point timeframe
    Up to 148 weeks
    End point values
    		 Simtuzumab Simtuzumab Placebo
    Number of subjects analysed
    137
    140
    Units: months
        median (confidence interval 95%)
    11.7 (9.9 to 15.9)
    14.3 (10.4 to 19.1)
    Statistical analysis title
    		 Statistical analysis - Simtuzumab vs Placebo
    Comparison groups
    Simtuzumab v Simtuzumab Placebo
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.851
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.43
    Notes
    [1] - The null hypothesis was that there is no difference in PFS between Simtuzumab and Simtuzumab placebo in participants with sLOXL2 ≥ 50th percentile. The alternative hypothesis was that there is a difference. These hypotheses were evaluated using stratified log-rank test, adjusted for screening post-bronchodilator FVC % predicted and concomitant use of pirfenidone or nintedanib (P/N) at time of screening.

    Primary: PFS Among the Participants With sLOXL2 ≥ 75th Percentile

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    End point title
    		 PFS Among the Participants With sLOXL2 ≥ 75th Percentile
    End point description
    Participants in the ITT Analysis Set with sLOXL2 ≥ 75th percentile in peripheral blood were analyzed.
    End point type
    Primary
    End point timeframe
    Up to 148 weeks
    End point values
    		 Simtuzumab Simtuzumab Placebo
    Number of subjects analysed
    68
    71
    Units: months
        median (confidence interval 95%)
    11.6 (9 to 15)
    16.9 (7.7 to 21.7)
    Statistical analysis title
    		 Statistical analysis - Simtuzumab vs Placebo
    Comparison groups
    Simtuzumab v Simtuzumab Placebo
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.475
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 2
    Notes
    [2] - The null hypothesis was that there is no difference in PFS between simtuzumab and simtuzumab placebo in participants with sLOXL2 ≥ 75th percentile. The alternative hypothesis was that there is a difference. These hypotheses were evaluated using stratified log-rank test, adjusted for screening post-bronchodilator FVC % predicted and concomitant use of pirfenidone or nintedanib (P/N) at time of screening.

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    1) Overall survival was defined as the time from randomization date to death that occurred prior to the last dose date plus 30 days. 2) ITT Analysis Set 3) 999 = not reached due to insufficient number of events
    End point type
    Secondary
    End point timeframe
    Up to 151 weeks
    End point values
    		 Simtuzumab Simtuzumab Placebo
    Number of subjects analysed
    272
    272
    Units: months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    Statistical analysis title
    		 Statistical analysis - Simtuzumab vs Placebo
    Comparison groups
    Simtuzumab Placebo v Simtuzumab
    Number of subjects included in analysis
    544
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.602
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 2.37

    Secondary: Relative Change From Baseline in FVC % Predicted

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    End point title
    		 Relative Change From Baseline in FVC % Predicted
    End point description
    • FVC was defined as the volume of air (liters) that can forcibly be blown out after taking a full breath. FVC % predicted was defined as FVC % of the participant divided by the average FVC % in the population for any person of similar age, sex, and body composition. • Adjusted means are from mixed model repeated measures (MMRM) model with baseline FVC % predicted, sLOXL2 level, concomitant pirfenidone/nintedanib use (never vs. ever), treatment, visit, and treatment-by-visit interaction terms, including all data up to Week 130. • Participants in the ITT Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Weeks 54, 106, and 130
    End point values
    		 Simtuzumab Simtuzumab Placebo
    Number of subjects analysed
    272
    272
    Units: percent change in FVC % predicted
    least squares mean (standard error)
        Wk 54 (Simtuzumab: N= 124; Placebo: N = 117)
    -9.2 ( 0.643 )
    -8.88 ( 0.658 )
        Wk 106 (Simtuzumab: N=60; Placebo: N= 55)
    -13.7 ( 0.883 )
    -12.16 ( 0.908 )
        Wk 130 (Simtuzumab: N=10; Placebo: N= 12)
    -18.09 ( 1.712 )
    -11.83 ( 1.6 )
    No statistical analyses for this end point

    Secondary: Number of Definite Acute Exacerbations of IPF Among Adjudicated Respiratory Hospitalizations

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    End point title
    		 Number of Definite Acute Exacerbations of IPF Among Adjudicated Respiratory Hospitalizations
    End point description
    End point type
    Secondary
    End point timeframe
    Participants in the ITT Analysis Set with adjudicated respiratory hospitalizations were analyzed.
    End point values
    		 Simtuzumab Simtuzumab Placebo
    Number of subjects analysed
    99
    84
    Units: Exacerbations per participant year
        number (not applicable)
    5
    5
    No statistical analyses for this end point

    Secondary: Number of Adjudicated Respiratory Hospitalizations (ARP) Among Total Hospitalizations

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    End point title
    		 Number of Adjudicated Respiratory Hospitalizations (ARP) Among Total Hospitalizations
    End point description
    Participants in ITT Analysis Set with total hospitalizations were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 148 weeks
    End point values
    		 Simtuzumab Simtuzumab Placebo
    Number of subjects analysed
    181
    154
    Units: Number of ARP
        number (not applicable)
    99
    84
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Adjudicated Respiratory Deaths Among Those With Adjudicated Death

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    End point title
    		 Number of Participants Experiencing Adjudicated Respiratory Deaths Among Those With Adjudicated Death
    End point description
    Participants in the ITT Analysis Set with adjudicated deaths were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 148 weeks
    End point values
    		 Simtuzumab Simtuzumab Placebo
    Number of subjects analysed
    19
    17
    Units: Participants
    17
    13
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in 6 Minute Walk Distance (6MWD)

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    End point title
    		 Absolute Change From Baseline in 6 Minute Walk Distance (6MWD)
    End point description
    • Adjusted means were from MMRM model with baseline 6MWD, FVC % predicted, sLOXL2 level, concomitant pirfenidone/nintedanib use (never vs. ever), treatment, visit, and treatment-by-visit interaction terms, including all data up to Week 130. • Participants in the ITT Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Weeks 58, 106, and 130
    End point values
    		 Simtuzumab Simtuzumab Placebo
    Number of subjects analysed
    272
    272
    Units: Meters
    least squares mean (standard error)
        Wk 58 (Simtuzumab: N= 95; Placebo: N= 98)
    -33.76 ( 6.617 )
    -14.7 ( 6.596 )
        Wk 106 (Simtuzumab: N= 44; Placebo: N= 37)
    -37.43 ( 9.71 )
    -24.3 ( 10.318 )
        Wk 58 (Simtuzumab: N= 7; Placebo: N= 9)
    -71.2 ( 19.14 )
    -31.65 ( 18.458 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Score

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    End point title
    		 Absolute Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Score
    End point description
    The SGRQ is a disease-specific questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. Patients respond to questions about symptoms (frequency & severity) and impact components (social functioning and psychological disturbances resulting from airways disease). Scores range from 0 to 100, with higher scores indicating more limitations.
    End point type
    Secondary
    End point timeframe
    Week 58, 106, and 130
    End point values
    		 Simtuzumab Simtuzumab Placebo
    Number of subjects analysed
    272
    272
    Units: units on a scale
    least squares mean (standard error)
        Wk 58 (Simtuzumab: N = 101; Placebo: N = 104)
    6.07 ( 1.015 )
    3.62 ( 1.01 )
        Wk 106 (Simtuzumab: N = 48; Placebo: N = 37)
    10.34 ( 1.425 )
    6.54 ( 1.559 )
        Wk 106 (Simtuzumab: N = 10; Placebo: N = 10)
    18.1 ( 2.424 )
    1.08 ( 2.473 )
    No statistical analyses for this end point

    Secondary: Overall Survival Among the Participants With sLOXL2 ≥ 50th Percentile

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    End point title
    		 Overall Survival Among the Participants With sLOXL2 ≥ 50th Percentile
    End point description
    1) Participants in the ITT Analysis Set with sLOXL2 ≥ 50th percentile in peripheral blood were analyzed. 2) 999 = not reached due to insufficient number of events
    End point type
    Secondary
    End point timeframe
    Up to 151 weeks
    End point values
    		 Simtuzumab Simtuzumab Placebo
    Number of subjects analysed
    137
    140
    Units: months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    Statistical analysis title
    		 Statistical analysis - Simtuzumab vs Placebo
    Comparison groups
    Simtuzumab v Simtuzumab Placebo
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.988
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 2.28
    Notes
    [3] - The difference in OS between the treatment groups was assessed using the stratified logrank test, adjusted for screening post-bronchodilator FVC % predicted and concomitant use of pirfenidone or nintedanib (P/N) at time of screening.

    Secondary: Overall Survival Among the Participants With sLOXL2 ≥ 75th Percentile

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    End point title
    		 Overall Survival Among the Participants With sLOXL2 ≥ 75th Percentile
    End point description
    1) Participants in the ITT Analysis Set with sLOXL2 ≥ 75th percentile in peripheral blood were analyzed. 2) 999 = not reached due to insufficient number of events
    End point type
    Secondary
    End point timeframe
    Up to 151 weeks
    End point values
    		 Simtuzumab Simtuzumab Placebo
    Number of subjects analysed
    68
    71
    Units: months
        median (confidence interval 95%)
    999 (19.2 to 999)
    999 (999 to 999)
    Statistical analysis title
    		 Statistical analysis - Simtuzumab vs Placebo
    Comparison groups
    Simtuzumab v Simtuzumab Placebo
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.925
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 2.99
    Notes
    [4] - The difference in OS between the treatment groups was assessed using the stratified logrank test, adjusted for screening post-bronchodilator FVC % predicted and concomitant use of pirfenidone or nintedanib (P/N) at time of screening.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    30 days post last study treatment (up to 148 weeks)
    Adverse event reporting additional description
    Safety Analysis Set: included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Simtuzumab
    Reporting group description
    		 Simtuzumab 125 mg/mL administered subcutaneously once a week

    Reporting group title
    Simtuzumab Placebo
    Reporting group description
    		 Simtuzumab placebo administered subcutaneously once a week

    Serious adverse events
    		 Simtuzumab Simtuzumab Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    101 / 271 (37.27%)
    97 / 272 (35.66%)
         number of deaths (all causes)
    31
    32
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchioloalveolar carcinoma
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal carcinoma
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 271 (0.37%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Metastases to lung
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 271 (0.37%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Squamous cell carcinoma of the tongue
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    2 / 271 (0.74%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    1 / 271 (0.37%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral artery occlusion
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 271 (0.37%)
    2 / 272 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Chest discomfort
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 271 (0.74%)
    3 / 272 (1.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 271 (0.74%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 271 (0.74%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 271 (0.74%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    6 / 271 (2.21%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cough
         subjects affected / exposed
    1 / 271 (0.37%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysponea
         subjects affected / exposed
    10 / 271 (3.69%)
    7 / 272 (2.57%)
         occurrences causally related to treatment / all
    1 / 12
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    3 / 271 (1.11%)
    2 / 272 (0.74%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    31 / 271 (11.44%)
    35 / 272 (12.87%)
         occurrences causally related to treatment / all
    3 / 40
    2 / 42
         deaths causally related to treatment / all
    1 / 9
    0 / 10
    Interstitial lung disease
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 271 (0.74%)
    3 / 272 (1.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 271 (0.37%)
    3 / 272 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    3 / 271 (1.11%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 271 (0.37%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    5 / 271 (1.85%)
    4 / 272 (1.47%)
         occurrences causally related to treatment / all
    1 / 5
    2 / 4
         deaths causally related to treatment / all
    0 / 1
    1 / 3
    Tachypnoea
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood urea increased
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural stroke
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    3 / 271 (1.11%)
    5 / 272 (1.84%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Acute right ventricular failure
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina pectoris
         subjects affected / exposed
    2 / 271 (0.74%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    6 / 271 (2.21%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 271 (0.74%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 271 (0.00%)
    2 / 272 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 271 (0.37%)
    3 / 272 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 271 (0.37%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuropericarditis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular dysfunction
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 271 (0.74%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic inflammatory demyelinating polyradiculoneuropathy
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Polyneuropathy
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Seizure
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 271 (0.74%)
    2 / 272 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Transient ischaemic attack
         subjects affected / exposed
    2 / 271 (0.74%)
    2 / 272 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIth nerve paralysis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric venous occlusion
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 271 (0.37%)
    2 / 272 (0.74%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 271 (0.00%)
    2 / 272 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    4 / 271 (1.48%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 271 (0.74%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic mass
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic necrosis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerulonephritis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Goodpasture's syndrome
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 271 (0.37%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylolysis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    2 / 271 (0.74%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 271 (0.74%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 271 (0.37%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 271 (0.00%)
    4 / 272 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycetoma mycotic
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngitis fungal
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Osteomyelitis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    16 / 271 (5.90%)
    18 / 272 (6.62%)
         occurrences causally related to treatment / all
    0 / 18
    0 / 18
         deaths causally related to treatment / all
    0 / 3
    0 / 4
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory moniliasis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 271 (0.00%)
    3 / 272 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 271 (0.37%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 271 (1.11%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Simtuzumab Simtuzumab Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    237 / 271 (87.45%)
    246 / 272 (90.44%)
    Investigations
    Weight decreased
         subjects affected / exposed
    25 / 271 (9.23%)
    24 / 272 (8.82%)
         occurrences all number
    25
    26
    Vascular disorders
    Hypertension
         subjects affected / exposed
    15 / 271 (5.54%)
    12 / 272 (4.41%)
         occurrences all number
    15
    13
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    31 / 271 (11.44%)
    26 / 272 (9.56%)
         occurrences all number
    35
    32
    Headache
         subjects affected / exposed
    32 / 271 (11.81%)
    35 / 272 (12.87%)
         occurrences all number
    45
    42
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    15 / 271 (5.54%)
    17 / 272 (6.25%)
         occurrences all number
    18
    18
    Chest pain
         subjects affected / exposed
    18 / 271 (6.64%)
    16 / 272 (5.88%)
         occurrences all number
    18
    16
    Fatigue
         subjects affected / exposed
    49 / 271 (18.08%)
    48 / 272 (17.65%)
         occurrences all number
    68
    54
    Injection site bruising
         subjects affected / exposed
    17 / 271 (6.27%)
    10 / 272 (3.68%)
         occurrences all number
    19
    12
    Pyrexia
         subjects affected / exposed
    21 / 271 (7.75%)
    12 / 272 (4.41%)
         occurrences all number
    24
    12
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    16 / 271 (5.90%)
    13 / 272 (4.78%)
         occurrences all number
    20
    13
    Diarrhoea
         subjects affected / exposed
    44 / 271 (16.24%)
    47 / 272 (17.28%)
         occurrences all number
    77
    71
    Gastrooesophageal reflux disease
         subjects affected / exposed
    21 / 271 (7.75%)
    22 / 272 (8.09%)
         occurrences all number
    21
    224
    Nausea
         subjects affected / exposed
    33 / 271 (12.18%)
    35 / 272 (12.87%)
         occurrences all number
    39
    43
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    102 / 271 (37.64%)
    93 / 272 (34.19%)
         occurrences all number
    134
    123
    Dyspnoea
         subjects affected / exposed
    98 / 271 (36.16%)
    73 / 272 (26.84%)
         occurrences all number
    122
    95
    Dyspnoea exertional
         subjects affected / exposed
    30 / 271 (11.07%)
    29 / 272 (10.66%)
         occurrences all number
    35
    32
    Epistaxis
         subjects affected / exposed
    16 / 271 (5.90%)
    9 / 272 (3.31%)
         occurrences all number
    19
    10
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    33 / 271 (12.18%)
    27 / 272 (9.93%)
         occurrences all number
    40
    32
    Oropharyngeal pain
         subjects affected / exposed
    16 / 271 (5.90%)
    15 / 272 (5.51%)
         occurrences all number
    22
    15
    Productive cough
         subjects affected / exposed
    22 / 271 (8.12%)
    18 / 272 (6.62%)
         occurrences all number
    28
    20
    Rhinorrhoea
         subjects affected / exposed
    19 / 271 (7.01%)
    15 / 272 (5.51%)
         occurrences all number
    23
    16
    Sputum increased
         subjects affected / exposed
    14 / 271 (5.17%)
    4 / 272 (1.47%)
         occurrences all number
    14
    4
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    17 / 271 (6.27%)
    8 / 272 (2.94%)
         occurrences all number
    20
    9
    Rash
         subjects affected / exposed
    22 / 271 (8.12%)
    21 / 272 (7.72%)
         occurrences all number
    25
    26
    Psychiatric disorders
    Depression
         subjects affected / exposed
    14 / 271 (5.17%)
    12 / 272 (4.41%)
         occurrences all number
    15
    13
    Insomnia
         subjects affected / exposed
    15 / 271 (5.54%)
    17 / 272 (6.25%)
         occurrences all number
    19
    17
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    35 / 271 (12.92%)
    22 / 272 (8.09%)
         occurrences all number
    41
    27
    Back Pain
         subjects affected / exposed
    27 / 271 (9.96%)
    28 / 272 (10.29%)
         occurrences all number
    31
    36
    Pain in extremity
         subjects affected / exposed
    9 / 271 (3.32%)
    14 / 272 (5.15%)
         occurrences all number
    13
    15
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    32 / 271 (11.81%)
    39 / 272 (14.34%)
         occurrences all number
    41
    53
    Lower respiratory tract congestion
         subjects affected / exposed
    8 / 271 (2.95%)
    15 / 272 (5.51%)
         occurrences all number
    13
    34
    Nasopharyngitis
         subjects affected / exposed
    36 / 271 (13.28%)
    43 / 272 (15.81%)
         occurrences all number
    44
    60
    Respiratory tract infection
         subjects affected / exposed
    14 / 271 (5.17%)
    17 / 272 (6.25%)
         occurrences all number
    26
    23
    Sinusitis
         subjects affected / exposed
    16 / 271 (5.90%)
    14 / 272 (5.15%)
         occurrences all number
    21
    16
    Upper respiratory tract infection
         subjects affected / exposed
    57 / 271 (21.03%)
    57 / 272 (20.96%)
         occurrences all number
    86
    91
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    29 / 271 (10.70%)
    34 / 272 (12.50%)
         occurrences all number
    31
    37

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Mar 2013
    • Clarification provided on collection time points for RNA biomarker samples • Updated table of contents to include new sections and ensure consistency in page/section numbers • Increased the number of study sites from 120 to 180 to support enrollment • Updated Study drug name from GS-6624 to the international non-proprietary name, simtuzumab • Updated all Gilead Sciences DSPH references for SAE reporting to PRA Safety
    11 Jun 2014
    • The primary endpoint was modified to include an additional primary endpoint of progression free survival in subjects with high serum levels of LOXL2 antibody. • Clarification of reversibility to reduce the risk of including subjects with reversible airway disease • Exclusion Criterion was modified to allow enrollment of subjects with certain cancers that have a low risk of reoccurrence. • Exclusion Criterion was updated to include the following text: “Concomitant use of pirfenidone or nintedanib is being allowed, but must be administered in accordance with the approved prescribing instructions in the country where the clinical trial site is located” . • The caps on the moderate and the severe strata were removed. • Revised the timing of the final analysis
    03 Sep 2015
    • Study subjects will have the option of continuing in an open-label rollover extension. • Duration of randomized, double-blind, placebo-controlled study was extended for up to 6 months after the accumulation of at least 250 PFS events. • Statistical components of the protocol were updated with respect to the testing strategy and handling of multiple comparisons which are aligned with the approved Statistical Analysis Plan. • Study visit procedures were added for the open-label phase of the study. • Editorial changes were made throughout the protocol, where appropriate, to improve clarity and consistency. • References to “pharmacogenomic” were updated to “genomic testing”. • Early Termination visit was revised to be scheduled “approximately 28 days after last dose of IMP”. • References to specific study visits at which procedures were performed were removed to avoid any confusion and inconsistencies in the protocol. • Corresponding changes to the protocol body text were also made in the Protocol Synopsis, where appropriate.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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